KR20090018979A - Sustained release pharmaceutical dosage form containing phenylephrine - Google Patents

Abstract

Pharmaceutical compositions comprising phenylephrine in a sustained release oral dosage formulation. Compositions can comprise phenylephrine alone or phenylephrine in combination additional pharmaceutically active substances such as an antihistamine and/or an analgesic.

Description

Sustained release pharmaceutical dosage form containing phenylephrine

The present invention relates to sustained release pharmaceutical dosage forms containing decongestant phenylephrine.

Phenylephrine and its pharmaceutically acceptable salts are recognized as safe and effective nasal decongestants. Commercial formulations include nasal jelly, nasal drops and nasal sprays (ie, Alconefrin ^R nasal drops or Neo-Synephrine ^R nasal jelly) as well as immediate release oral tablets or gelatins. Capsules (ie, Sudafed PE ^™ or DayQuil ^R LiquidCaps). Phenylephrine or a pharmaceutically acceptable salt as recently formulated is typically administered every 4 hours to relieve nasal congestion due to the short half-life of phenylephrine. Accordingly, there is a need for slow release formulations of phenylephrine that can be administered less frequently, for example, once every 8 hours, once every 12 hours, or possibly once every 24 hours.

Sustained release formulations reduce the frequency of drug administration to improve patient compliance. In addition, sustained release drug systems result in a constant therapeutic plasma level of the active ingredient compared to the variation seen when multiple doses of conventional formulations are provided. Sustained release drugs can reduce the severity and frequency of side effects from multiple doses or pulse release systems.

US Pat. No. 4,792,452 describes tablet formulations consisting of up to about 45% by weight of pH-dependent salts of alginic acid, up to about 35% by weight of pH-independent hydrocolloid gelling agents, binders and excipients. Thus, the release of the drug is affected by various pH of the gastrointestinal tract. Australian patent application AU-B-56761 / 86 describes examples of sustained release formulations for aspirin and theophylline comprising certain hydroxypropylmethylcellulose. AU-B-56761 / 86 also describes phenylephrine as one of at least 27 drugs or types of drugs that are typical sensitizing drugs. Japanese Patent 2005-60294 describes stabilized compositions of phenylephrine containing carbinoxamine and various salts.

Decongestants are usually administered orally with antihistamines to relieve nasal congestion associated with allergic rhinitis. Antihistamines with long half-lives compared to phenylephrine are known. If the decongestant is phenylephrine or a pharmaceutically acceptable salt thereof, and the antihistamine is a long-acting antihistamine, the dosage form is preferably released in a conventional manner and the phenylephrine is pharmaceutical The composition should be designed to be sustained release to be suitable for administration for at least 8 hours.

Loratadine is described in US Pat. No. 4,282,233 as a non-sedative antihistamine, eg useful for the relief of seasonal allergic rhinitis, such as sneezing and itching, and for the treatment of chronic idiopathic urticaria in patients older than 6 years. Loratadine is available in the form of conventional tablets that release loratadine in a conventional manner by disintegration and dissolution processes so that loratadine begins to exhibit its antihistamine effect within 1 to 3 hours and lasts longer than 24 hours. Do. Thus, tablets are administered orally only once daily. Azatadine is described in Belgian patent 647,043 and corresponding US patents 3,326,924 and 3,419,565. Loss half-life is reported to be 9-12 hours. Terpenadine and fexofenadine are described in US Pat. No. 3,878,217 and have a duration of action of 12 to 24 hours, and at least 24 hours, respectively. Cetirizine described in US Pat. No. 4,525,358; The asemizol described in US Pat. No. 4,219,559 and the levocarvastin described in US Pat. No. 4,369,184 have durations of action of 12 to 24 hours, at least 24 hours and 16 to 24 hours, respectively.

It is an object of the present invention to provide an oral sustained release pharmaceutical composition which releases phenylephrine or a pharmaceutically acceptable salt thereof over at least 8 hours, preferably at least 12 hours, more preferably at least 24 hours. will be.

Another object of the present invention is to provide a therapeutically effective amount of phenylephrine or a pharmaceutically acceptable salt thereof for combination administration, and additional therapeutic compositions with a natural half-life longer than phenylephrine, such as antihistamines. It is to provide a pharmaceutical composition providing a dosage form.

These and other objects of the present invention are met by the present invention described and claimed below, which provides a single dose of phenylephrine to achieve a distribution over 8 hours or more. As described in the Examples below, one aspect of the present invention has been demonstrated to provide a single dose of phenylephrine that is bioequivalent to two doses of the immediate release phenylephrine provided at 4 hour intervals. . In addition, formulations prepared according to the invention are stable and have a half-life of at least two years. Formulations according to the invention may comprise phenylephrine alone or in combination with additional pharmaceutical active agents including antihistamines, analgesics and the like.

The gist of the invention

Accordingly, the present invention comprises a core comprising phenylephrine or a pharmaceutically acceptable salt thereof in a sustained release matrix and further comprising at least one hydrophilic or hydrophobic polymer outside of the core. Pharmaceutical compositions in dosage forms are provided.

Further, the present invention is obtained when two doses of a standard immediate release formulation comprising phenylephrine in a polymer matrix comprising hydroxypropyl methylcellulose and comprising 10 mg of phenylephrine in a human subject is obtained. the discharging standing, the printer capacity is available -phenyl a single dose showing a 50% to 125% identical mean AUC and / or C _max and a therapeutically effective for at least 8 hours after administration to a human subject of the AUC and / or C _max To provide a pharmaceutical composition formulated for. In a preferred embodiment, such compositions have, on human subjects, an average equal to 80% to 125% of the AUC and / or C _max obtained when administering two doses of a standard immediate release formulation comprising 10 mg of phenylephrine. AUC and / or C _max .

Further, the present invention is obtained when three doses of a standard immediate release formulation comprising phenylephrine in a polymer matrix comprising hydroxypropyl methylcellulose and comprising 10 mg of phenylephrine in a human subject is obtained. the discharging standing, the printer capacity is available -phenyl a single dose showing a 50% to 125% identical mean AUC and / or C _max and a therapeutically effective for at least 12 hours after administration to a human subject of the AUC and / or C _max To provide a pharmaceutical composition formulated for. In a preferred embodiment, such a composition has an average of equal to 80% to 125% of the AUC and / or C _max obtained when administering three doses of a standard immediate release formulation comprising 10 mg of phenylephrine in a human subject. AUC and / or C _max .

In addition, the present invention is obtained when six doses of a standard immediate release formulation comprising phenylephrine in a polymer matrix comprising hydroxypropyl methylcellulose and comprising 10 mg of phenylephrine in a human subject is obtained. to release up the printer capacity is valid phenyl therapeutically for at least 24 hours after a single dose showing the same mean AUC and / or C _max and 50% to 125% of the administered to a human subject of the AUC and / or C _max Formulated pharmaceutical compositions are provided. In a preferred embodiment, such a composition has, on human subjects, an average equal to 80% to 125% of the AUC and / or C _max obtained when administering six doses of a standard immediate release formulation comprising 10 mg of phenylephrine. AUC and / or C _max .

In addition, the present invention, when administered to a subject once, 50% of the average AUC and / or C _max represented by the two doses of the pharmaceutical composition containing 10 mg of phenylephrine and no sustained release polymer matrix. Provided is a pharmaceutical composition comprising phenylephrine or a pharmaceutically acceptable salt thereof in a sustained release polymer matrix, which exhibits an average AUC and / or C _{max above} . In a preferred embodiment, such compositions, when administered to a subject once, average AUC and / or C _{max as} represented by two doses of the pharmaceutical composition containing 10 mg of phenylephrine and no sustained release polymer matrix. Mean AUC and / or C _{max of} at least 80%.

In addition, the present invention provides an average of 50 AUC and / or C _max as represented by three doses of a pharmaceutical composition, which, when administered to a subject once, contains 10 mg of phenylephrine and no sustained release polymer matrix. A pharmaceutical composition is provided comprising phenylephrine or a pharmaceutically acceptable salt thereof in a sustained release polymer matrix that exhibits an average AUC and / or C _{max of} at least%. In a preferred embodiment, such compositions, when administered to a subject once, average AUC and / or C _{max as} represented by three doses of the pharmaceutical composition containing 10 mg of phenylephrine and no sustained release polymer matrix. Mean AUC and / or C _{max of} at least 80%.

In addition, the present invention, when administered to a subject once, 50% of the average AUC and / or C _max represented by six doses of the pharmaceutical composition containing 10 mg of phenylephrine and no sustained release polymer matrix. Provided is a pharmaceutical composition comprising phenylephrine or a pharmaceutically acceptable salt thereof in a sustained release polymer matrix, which exhibits an average AUC and / or C _{max above} . In a preferred embodiment, such compositions, when administered to a subject once, average AUC and / or C _{max as} represented by six doses of the pharmaceutical composition containing 10 mg of phenylephrine and no sustained release polymer matrix. Mean AUC and / or C _{max of} at least 80%.

In addition, the present invention provides that up to 30% of phenylephrine or a pharmaceutically acceptable salt thereof is released from the pharmaceutical composition within 1 hour, and up to 60% of phenylephrine or its pharmaceutically acceptable salt is pharmaceutical within 4 hours. Released from the pharmaceutical composition, up to 90% of phenylephrine or a pharmaceutically acceptable salt thereof is released from the pharmaceutical composition within about 8 hours, and at least 99% of the phenylephrine or pharmaceutically acceptable salt thereof is about 24 hours Provided is a pharmaceutical composition comprising phenylephrine or a pharmaceutically acceptable salt thereof, which exhibits sustained release of phenylephrine from the composition when contacted with USP simulated intestinal fluid to be released from the pharmaceutical composition.

1: Release profile of phenylephrine HCl from tablets over 24 hours. Dissolution studies were performed with USP simulated sera using a stirring USP Apparatus II set at 50 rpm. At each time interval, solution samples were analyzed to determine the percentage of phenylephrine HCl dissolved.

FIG. 2: Bioequivalence Study comparing a single dose of 30 mg phenylephrine in four tablets according to the present invention with two lOmg phenylephrine immediate release tablets (reference product S) administered at 4 hour intervals. mean plasma concentration over 24 hours from the bioequivalence study.

Figure 3: From bioequivalence studies comparing a single dose of 30 mg phenylephrine in four tablets according to the invention (test product B) compared to two lOmg phenylephrine immediate release tablets (reference product S) administered at 4 hour intervals. Average plasma concentration over 24 hours on the semi-logarithmic scale of.

The present invention provides pharmaceutical formulations of solid dosage forms comprising phenylephrine or a pharmaceutically acceptable salt thereof and one or more sustained release polymers together with excipients that provide a composition that releases phenylephrine over a period of about 8 hours or more. To provide a composition. The composition according to the invention is biologically equivalent to at least two standard release dosage forms provided at four hour intervals as measured by C _max and AUC for serum analysis in human subjects. In a preferred embodiment, the invention is biologically equivalent to at least three standard release dosage forms provided at four hour intervals as measured by C _max and AUC for serum analysis in human subjects. In a further preferred embodiment, the composition according to the invention is biologically equivalent to at least six standard release dosage forms provided at four hour intervals as measured by C _max and AUC for serum analysis in human subjects.

The term "biologically equivalent" as used herein in connection with a preferred embodiment is used in accordance with commonly understood meanings, ie 80% to 125 of C _max and AUC for serum analysis in human subjects in standard release dosage forms. A composition representing% is meant.

According to one embodiment of the present invention, large amounts of phenylephrine are formulated for slow release in the tablet core. The term sustained release, as used herein, refers to the use of an active agent from a pharmaceutical composition such that the active agent is made available for bioabsorption over a prolonged period of time in the subject, primarily a subject's gastrointestinal tract, eg, about 1 to about 24 hours or more. Indicates release. In certain embodiments of the compositions of the invention, the time period will be at least about 8 hours, at least about 12 hours or at least about 24 hours. The term sustained release also includes what is otherwise referred to as extended release, controlled release or sustained delivery. The release rate of the active agent is controlled primarily by dissolution of the active agent in intestinal fluids and diffusion from tablets independent of pH, and may also be affected by the physical process of disintegration and erosion of the tablets. Due to the relatively short half-life of phenylephrine, the therapeutic blood serum concentration of phenylephrine is mainly the result of the release of phenylephrine from the tablets over an extended period of time. The formulations according to the invention provide a single dose of phenylephrine to achieve a therapeutic blood serum concentration of phenylephrine in a subject in need thereof for an extended period of time to provide a therapeutic effect of phenylephrine in the subject. In another preferred embodiment of the invention, phenylephrine is released from the tablet to result in therapeutic blood serum concentrations for at least 8 hours or at least 12 hours or at least 24 hours from a single dose. The release rate from the tablet is independent of pH but very dependent on the solubility profile of phenylephrine. Active agents other than phenylephrine have different release rates than phenylephrine and thus are not a precursor to the compositions according to the invention.

In a preferred embodiment, phenylephrine is used in combination with additional active ingredients. When phenylephrine is used in combination with antihistamines, the antihistamines may be H ₁ or H ₂ antagonists or other types of histamine release inhibitors. The H ₁ antagonist may be soothing or non-sedative, such as diphenhydramine, chlorpheniramine, tripelinamine, promethazine, clemastine, doxylamine, astemizol, terpenadine and loratadine. Examples of H ₂ antagonists include, but are not limited to, cimetadine, pamotidine, nizatidine and ranitidine. Examples of histamine-releasing inhibitors include, but are not limited to, chromoline.

If any active ingredient (s) used have a water solubility similar to phenylephrine, it may be located in the core of the tablet, ie in the polymer matrix for controlled release. In a further embodiment, any active ingredient (s) has a longer half-life than phenylephrine and does not require controlled release, but it is released at a rapid or immediate release rate, whereas phenylephrine is released at a sustained rate. In such cases, any active ingredient (s) may be located outside the core of the tablet.

In addition, the core of the tablet may comprise additional pharmaceutically acceptable inert carrier materials. The term pharmaceutically acceptable carrier refers to a nontoxic solid, semisolid or liquid filler, diluent, encapsulating material or any type of formulation aid. Suitable pharmaceutical carriers are described in the literature; Gennaro et al., (1995) Remington's Pharmaceutical Sciences, Mack Publishing Company. In a preferred embodiment, the carrier material is a solid pharmaceutical excipient such as starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, magnesium stearate, sodium stearate, Glycerol monostearate, sodium chloride, dried skim milk, and the like. In a preferred embodiment, the core of the pharmaceutical composition of the invention is lactose, which may be of pharmaceutically acceptable grade, including, for example, β-lactose, anhydrous α-lactose, α-lactose monohydrate. It further includes. In certain instances, the moisture content of the materials used in the formulation of the pharmaceutical composition is controlled, providing long term stability for at least 1 year, 2 years, 3 years or more, and / or microbial growth during long term storage. It can be important to adjust. In such instances, anhydrous forms of the carrier material may be preferred.

The sustained release polymer that occupies the core of the tablet is hydroxypropyl methylcellulose. Sustained release polymers are present in an amount of about 15-50%, preferably about 20-40%, more preferably about 25-35%, even more preferably about 29-31% by weight of the tablet. May exist. According to one embodiment of the invention, the sustained release polymer comprises hydroxypropyl methylcellulose in an amount of about 3% by weight of the total weight of the tablet. In a preferred embodiment, the sustained release polymer is combined with lactose as the main component of the tablet. For example, for tablets comprising about 30% by weight hydroxypropyl methylcellulose and about 4% by weight hydroxypropylcellulose, about 59.5% by weight of the tablet may be lactose.

Examples of hydroxypropyl methylcellulose polymers that can be used in the present invention are Dow Chemical Campa, Michigan, USA under the trade names Methocel, for example, Methocel KlOOM CR, Methocel K3, Methocel K15M, etc. Commercially available from Dow Chemical Co. Hydroxypropyl methylcellulose is also known as hypromellose.

As an example of a binder material, for example, from Aqualon, Delaware, Delaware, USA under the trade names Klucel ^™ , for example, Klucel EXF ^™ , Klucel JF ^™ , Klucel HF ^™ Commercially available and commercially available from Nippon Soda Co., Ltd., Tokyo, Japan under the trade names Nisso HPC ^™ , such as HPC-L ^™ , HPC-M ^™, etc. Hydroxypropylcellulose polymers, including those that can be used, can be used in the present invention. Hydroxypropylcellulose may be present in the compositions of the present invention in an amount of about 10% or less, preferably about 7.5% or less, more preferably about 4% or less by weight of the total weight of the composition. In addition to hydroxypropyl cellulose, additional cellulose ethers such as sodium carboxymethyl cellulose, xanthan gum, acacia, tragacanth gum, guar gum, karaya gum, alginate, gelatin, albumin and the like, and other water soluble or swellable polymers. May be present outside the core in the tablet.

Dosage forms according to the invention are solid and may take the usual forms for oral administration such as tablets, pills, capsules and the like. Preferred examples of solid dosage forms are compressed tablets. Dosage forms according to the invention may further contain standard excipients such as disintegrants, glidants, binders and anti-sticking agents.

Sustained release formulations of the invention include lubricants such as magnesium stearate, potassium stearate, zinc stearate, powdered stearic acid, hydrogenated vegetable oils, talc, polyethylene glycols and mineral oils; Colorants such as various FD & C colors; Binders such as sucrose, lactose, gelatin, starch paste, acacia, tragacanth, povidone, polyethylene glycol, pullulan and corn syrup; Glidants such as colloidal silicon dioxide and talc; Surface active agents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, triethanolamine, polyoxyethylene sorbitan, poloxalchol and quaternary ammonium salts; Preservatives and stabilizers; Excipients such as lactose, mannitol, glucose, fructose, xylose, galactose, sucrose, maltose, xylitol, sorbitol, chlorides, sulfates and phosphate salts of potassium, sodium and magnesium; And / or other pharmaceutical additives known to those skilled in the art, such as, but not limited to, microcrystalline cellulose or dicalcium phosphate. Standard tablet excipients may be included in the formulations according to the invention.

Optionally, blends of phenylephrine, sustained release polymer and excipients can be converted to granules by conventional means. For example, a wet granulation process comprising alcohol can be used. In one embodiment, the tablets dry blend and granulate the active ingredient with excipients, add antioxidants, chelating agents, moisture scavengers or other stabilizing aids such as magnesium stearate and granulate / compress Controlled moisture levels in the product to prevent phenylephrine degradation, to separate the phenylephrine salt from the wet granulation process and to incorporate the active ingredient into the process by dry granulation or mixing or coated phenyl It is prepared using ephrin. Tablets can be formed using direct compression and other conventional methods. Optionally, the blend or granulated blend can be compressed into a core and coated with a polymeric film.

Stability and degradation analyzes are described in the literature to simulate shelf life of two years or more. It can be performed according to the International Conference on Harmonization (ICH) as described in the "Impurities in New Drug Products" guidelines. For example, the stability test can be performed at 40 ° C./75% relative humidity for three months. Standard pharmaceutical storage conditions are known in the art. The compositions according to the invention can be analyzed to meet all ICH guidelines for active pharmaceutical analysis with degradation levels below the reporting limit, preferably below the identification limit, most preferably below the quantification limit.

In addition, the present invention provides a pharmaceutical composition comprising phenylephrine or a pharmaceutically acceptable salt thereof, which exhibits slow release of phenylephrine from the composition when in contact with USP simulated serous fluid. In this aspect of the invention, the pharmaceutical composition is formulated so that when tested in an in vitro method simulating in vivo conditions, the pharmaceutical composition can be analyzed to demonstrate sustained release of phenylephrine from the composition. . In one embodiment, the pharmaceutical composition will provide sustained release for at least 8 hours so that less than the total amount of phenylephrine can be determined to be dissolved in USP simulated intestinal fluid over at least 8 hours. In further embodiments, the time is at least 12 hours, at least 16 hours, at least 20 hours or at least 24 hours.

In a preferred embodiment, the composition is released from the pharmaceutical composition within 1 hour of contacting up to 30% of phenylephrine or a pharmaceutically acceptable salt thereof with USP simulated intestinal fluid, and 60% of phenylephrine or a pharmaceutically acceptable salt thereof. Less than 4% is released from the pharmaceutical composition within 4 hours, and less than 90% of the phenylephrine or pharmaceutically acceptable salt thereof is released from the pharmaceutical composition within about 8 hours, and less than of phenylephrine or pharmaceutically acceptable salt thereof At least 99% show sustained release of phenylephrine to be released from the pharmaceutical composition within about 24 hours.

The subject to which the composition according to the present invention is administered is not limited. Dosage depends on the size and age of the patient, the severity of the symptoms, and the like. Administration is preferably carried out by adjusting the dosage based on various factors contemplated by one of ordinary skill in the art, including the age, body weight, previous dose response of the subject, preferably 1 day Administration is once or twice.

The invention is illustrated by the following examples. Still other methods will be apparent to those skilled in the art, which are deemed to be within the scope of this invention, and therefore, the examples should not be construed as limiting the invention.

Example 1: Tablet Formulation

Tablets were prepared from the following ingredients:

Lactose Monohydrate 297.5 mg

Metocell KlOOM CR ¹ 150.0mg

Phenylephrine HCl 30.0mg

Klucel EXF ² 20.0mg

Magnesium Stearate 2.5mg

Total: 500.0mg

¹ : hydroxypropyl methylcellulose (hypromellose) 2208, 19-24% methoxyl content, 7-12% hydroxypropyl content.

² : hydroxypropyl cellulose.

Phenylephrine HCl was passed through a 30 mesh screen. Lactose monohydrate, Methocel KlOOM CR, Phenylephrine HCl and Klucel EXF were charged to the blender and blended until uniform. Half of the magnesium stearate was passed through a 30 mesh screen and added to a blender containing a homogeneous mixture and blended for an additional 1-3 minutes. The resulting mixture was granulated with a roller / compressor, sized with a mill and blended for an additional 1-3 minutes. The remaining magnesium stearate was passed through a 30 mesh screen and blended with the mixture for an additional 1-3 minutes. The mixture was compressed to tablets. In another procedure, the entire amount of magnesium stearate was passed through a 30 mesh screen and charged to the mixture in the blender in a single step. The mixture was blended for 1 to 3 minutes and the resulting granules were compressed to tablets.

Example 2: Tablet Dissolution Profile

The release profile of phenylephrine HCl from the tablets according to Example 1 was studied over 24 hours. Dissolution studies were performed with USP simulated sera using a stirring USP Apparatus II set at 50 rpm. At each time interval, a sample of the solution was analyzed to determine the percentage of phenylephrine HCl dissolved. 1 graphically depicts the data.

Dissolution profile Hours (hr) Dissolution rate (%) 1 2 4 8 12 16 24 28.5 42.7 61.5 83.3 94.5 99.7 103.2

Example 3: Bioequivalence Study

Bioequivalence is an approved guideline (see literature; Food and Drug Administration, Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products-General Considerations, Center for Drug Evaluation and Research, March 2003, and references; Food and Drug Administration, Statistical Approaches to Establishing Bioequivalence, Center for Drug Evaluation and Research, January 2001). In the study, a single dose of 30 mg phenylephrine in a tablet according to the invention was compared to two 10 mg phenylephrine immediate release tablets (Sudapede PE ^™ nasal decongestant tablets 10 mg) administered at 4 hour intervals. 24 healthy volunteers participated in the study. On day 1 of the study, subjects were randomly administered a single oral dose of test tablet or two doses of comparative tablet. After intestinal washout on day 3, the subject recovered and randomized to receive another treatment. Drug administration was used using 240 mL of ambient temperature water.

During each study period, 29 blood samples (6 mL each) were collected from each subject at the following time points: 1 hour prior to dosing (0 hour) and 0.25, 0.5, 0.75, 1, 1.25, 1.5 doses administered. , 1.75, 2, 3, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22 and 24 hours later. Overall, phenylephrine is well tolerated as two 10 mg immediate release tablets administered continuously at four hour intervals when administered under fasted conditions or as a single oral dose of 30 mg 8 hour extended release tablet. 2 and 3 show the results graphically. A summary of statistical analysis is shown in Tables 2-4.

Summary of Ln-Modified Pharmacodynamic Parameters Phenylephrine Ln-modified C _max Ln-modified AUC _0-t Ln-Modified AUC _0-∞ Test product arithmetic mean 82.83 329.98 392.00 Reference product arithmetic mean 89.28 356.81 450.68 % Rain 92.77 92.48 86.98 90% confidence interval (86.22, 99.82) (96.6, 98.76) (80.84, 93.59)

Summary of Pharmacodynamic Parameters Phenylephrine C _max AUC _0-t AUC _0-∞ Test Product Least Squares Mean 86.26 346.94 412.34 Reference product least squares mean 92.04 363.35 469.51 % Rain 93.72 95.48 87.82 90% confidence interval (87.22, 100.22) (89.79, 101.17) (80.29, 95.35)

Summary of Pharmacodynamic Parameters Phenylephrine T _max ^* K _e t _1/2 C _t Test Product Least Squares Mean NA 0.3500 2.09 5.80 Reference product least squares mean NA 0.4802 1.60 5.88 % Rain NA 72.89 129.99 98.67 90% confidence interval NA (60.05, 85.72) (109.4, 150.58) (97.55, 99.79)

^The p value (<0.0001) for T _max is based on the Wilcoxon Rank Sum Test.

The 90% confidence interval for the ratio of the test arithmetic mean to the baseline mean is within the 80% and 125% limits for the pharmacodynamic parameters C _max , AUC _0-t and AUC _∞ of the In _- modified data.

The relevant parameters are understood as follows:

Peak drug concentrations obtained directly from the data without C _max interpolation.

T _max Time to peak drug concentration obtained directly from data without interpolation.

C _t final measured plasma concentration; Final concentration higher than low LOQ after dosing.

Terminal or elimination rate constant determined from the slope of the drug concentration-time curve using linear regression at the end data point of the λ _z (k _elim ) curve.

The area under the concentration-time curve from 0 to time t, calculated by the AUC _0-t trapezoidal rule, where t is the end point of the measurable concentration.

AUC _0-∞ Area under the concentration-time curve from time 0 to time infinity, calculated as follows: AUC _0-∞ = AUC _0-t + C _t / λ _z

Where _Ct is the final measurable drug concentration and λ _z is the end or loss rate constant.

t _1/2 The end or loss half-life of the drug, calculated from the following equation:

t _1/2 = In (2) / λ _z

Example 4-Double Release Phenylephrine Sustained-Release Tablet.

The following practice provides pharmaceutical formulations comprising phenylephrine in two portions, wherein the first portion comprises an immediate release formulation and the second portion is about 0 or near zero order sustained release formulation. 18 to 22 mg phenylephrine. The immediate release layer may be an active coating or an immediate release layer of two or three layered tablets. The zero or near zero order sustained release portion may be a core tablet or a layer of two or three layered tablets.

Thus, the composition may comprise the next sustained release portion and the immediate release portion.

Slow release part:

ingredient Weight% range Phenylephrine Hydrochloride 1-50 Microcrystalline Cellulose NF 0-60 Carboxymethylcellulose Sodium or Calcium Salt 10-60 Hydroxypropyl cellulose 20-40 Colloidal silicon dioxide 0-2 Magnesium stearate 0.2-2.0

Three part immediate release coating:

Part A: Sealing Coating:

ingredient Target weight (g / tablet) % Target weight in solution (w / w) Water USP 0.00 0.00 Polyethylene Glycol 3350 1.67 2.28 & Methocel E-5 Premium LV 8.33 11.36% gun 1.00 13.64%

Part B: Active coating (assume 10 mg of PE in the coating)

ingredient Target weight (g / tablet) % Target weight in solution (w / w) Water USP 0.00 0.00 Polyethylene Glycol 3350 3.65 1.35% Methocel E-5 Premium LV 14.60 5.38% Loratadine 5.00 1.84% Opaspray Blue K-1-4108 ^* 8.20 3.02% Phenylephrine HCl 150 Mesh 10.00 3.69% gun 41.45 15.28%

Further information on active coatings (B): possible ranges for PE

ingredient Target weight (g / tablet) % Target weight in solution (w / w) Phenylephrine HCl 150 Mesh 8.00 3.10% Phenylephrine HCl 150 Mesh 12.00 4.22%

Part C: Sealing Coating:

ingredient Target weight (g / tablet) % Target weight in solution (w / w) Water USP 0.00 0.00 Polyethylene Glycol 400 0.75 2.27% Methocel E-5 Premium LV 3.75 11.37% gun 4.50 13.64%

The results shown in the examples and figures are non-limiting. From the foregoing description, the essential features of the invention can be ascertained, and the invention can be variously modified and modified to suit various uses and conditions without departing from the spirit and scope thereof.

Claims (28)

Pharmaceutical formulations of solid dosage forms for oral administration comprising a core comprising phenylephrine or a pharmaceutically acceptable salt thereof in a sustained release matrix and further comprising at least one hydrophilic or hydrophobic polymer on the exterior of the core. Composition. The composition of claim 1, wherein the sustained release matrix comprises hydroxypropyl methylcellulose. The composition of claim 1, wherein the core exhibits increased resistance to disintegration and erosion in the gastrointestinal tract such that the core can sustain release of phenylephrine or a pharmaceutically acceptable salt thereof for at least 8 hours. The composition of claim 1, wherein the core exhibits increased resistance to disintegration and erosion in the gastrointestinal tract such that the core can sustain release of phenylephrine or a pharmaceutically acceptable salt thereof for at least 12 hours. The composition of claim 1, wherein the core exhibits increased resistance to disintegration and erosion in the gastrointestinal tract such that the core can sustain release of phenylephrine or a pharmaceutically acceptable salt thereof for at least 24 hours. The composition of claim 1 wherein the hydrophilic or hydrophobic polymer is selected from the group consisting of water soluble cellulose ethers, polyethylene oxides and mixtures thereof. The composition of claim 1 further comprising one or more pharmaceutically acceptable excipients. The method of claim 5 wherein the water soluble cellulose ether is selected from the group consisting of methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose and mixtures thereof Composition. The composition of claim 1 wherein the hydrophobic polymer is crosslinked acrylic acid. The composition of claim 1 wherein phenylephrine or a pharmaceutically acceptable salt thereof comprises about 1 to 25% of the weight of the tablet and hydroxypropyl methylcellulose comprises about 10 to 50% of the weight of the tablet. The composition of claim 1, which is stable for at least two years under standard pharmaceutical storage conditions. 80% to 125% of the AUC and / or C _max obtained when administering two doses of a standard immediate release formulation comprising phenylephrine in a polymer matrix and comprising 10 mg of phenylephrine in a human subject; A pharmaceutical composition formulated to sustain release a therapeutically effective phenylephrine dose for at least 8 hours after administration of a single dose to a human subject, exhibiting the same mean AUC and / or C _max . 80% of the AUC and / or C _max obtained when administering three doses of a standard immediate release formulation comprising phenylephrine in a sustained release polymer matrix and comprising 10 mg of phenylephrine in a human subject A pharmaceutical composition formulated to sustain release a therapeutically effective phenylephrine dose for at least 12 hours after administration of a single dose to a human subject, with an average AUC and / or C _max equal to 125%. 80% to 125% of the AUC and / or C _max obtained when six doses of a standard immediate release formulation comprising phenylephrine in a polymer matrix and comprising 10 mg of phenylephrine in a human subject; A pharmaceutical composition formulated to sustain release a therapeutically effective phenylephrine dose for at least 24 hours after administration of a single dose to a human subject, exhibiting the same mean AUC and / or C _max . When administered to a subject once, an average AUC that is at least 80% of the average AUC and / or C _max represented by the two doses of the pharmaceutical composition containing 10 mg of phenylephrine and no sustained release polymer matrix. Or phenylephrine or a pharmaceutically acceptable salt thereof in a sustained release polymer matrix, which represents C _max . When administered to a subject once, an average AUC that is at least 80% of the average AUC and / or C _max represented by three doses of the pharmaceutical composition containing 10 mg of phenylephrine and no sustained release polymer matrix. Or phenylephrine or a pharmaceutically acceptable salt thereof in a sustained release polymer matrix, which represents C _max . When administered to a subject once, an average AUC that is at least 80% of the average AUC and / or C _max represented by the six doses of the pharmaceutical composition containing 10 mg of phenylephrine and no sustained release polymer matrix. Or phenylephrine or a pharmaceutically acceptable salt thereof in a sustained release polymer matrix, which represents C _max . The composition of claim 12, wherein the sustained release polymer matrix comprises hydroxypropyl methylcellulose. The composition of claim 1 comprising an additional therapeutic agent. The composition of claim 19, wherein the additional therapeutic agent is located outside the core. The composition of claim 18, wherein the additional therapeutic agent is selected from the group consisting of antihistamines, analgesics, and combinations thereof. The method of claim 19, wherein the antihistamine is diphenhydramine, chlorpheniramine, tripelinamine, promethazine, clemastine, doxylamine, astemizol, terpenadine, loratadine, cimetadine, pamotidine, nizatidine. , Ranitidine, chromoline, and combinations thereof. A pharmaceutical composition comprising phenylephrine or a pharmaceutically acceptable salt thereof, which exhibits slow release of phenylephrine from the composition when in contact with USP simulated serous fluid. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition provides sustained release for at least 8 hours so that less than the total amount of phenylephrine can be determined to be dissolved in USP simulated intestinal fluid over at least 8 hours. Up to 30% of phenylephrine or a pharmaceutically acceptable salt thereof is released from the pharmaceutical composition within 1 hour, and up to 60% of phenylephrine or a pharmaceutically acceptable salt thereof is released from the pharmaceutical composition within 4 hours, Up to 90% of phenylephrine or a pharmaceutically acceptable salt thereof is released from the pharmaceutical composition within about 8 hours, and at least 99% of phenylephrine or a pharmaceutically acceptable salt thereof is released from the pharmaceutical composition within about 24 hours. Preferably, the pharmaceutical composition comprises phenylephrine or a pharmaceutically acceptable salt thereof, which exhibits slow release of phenylephrine from the composition when contacted with USP simulated serous fluid. The composition of claim 25 comprising an additional therapeutic agent. The composition of claim 26, wherein the additional therapeutic agent is selected from the group consisting of antihistamines, analgesics, and combinations thereof. The method of claim 27, wherein the antihistamine agent is diphenhydramine, chlorpheniramine, tripelinamine, promethazine, clemastine, doxylamine, astemizol, terpenadine, loratadine, cimettadine, pamotidine, nizatidine , Ranitidine, chromoline, and combinations thereof.

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